In diseases such as osteoarthritis and rheumatism, destruction of the joint takes place, with this destruction being caused, in particular, by the proteolytic breakdown of collagen due to collagenases. Collagenases belong to the metalloproteinase (MP) or matrix metalloproteinase (MMP) superfamily. The MMPs form a group of Zn-dependent enzymes which are involved in the biological breakdown of the extracellular matrix (D. Yip et al. in Investigational New Drugs 17 (1999), 387–399 and Michaelides et al. in Current Pharmaceutical Design 5 (1999) 787–819). These MMPs are, in particular, able to break down fibrillar and nonfibrillar collagen and also proteoglycans, both of which are important matrix constituents. MMPs are involved in processes of wound healing, tumor invasion and metastasis migration, and also in angiogenesis, multiple sclerosis and heart failure (Michaelides, page 788; see above). In particular, they play an important role in the breakdown of the joint matrix in arthrosis and arthritis, whether this be osteoarthrosis, osteoarthritis or rheumatoid arthritis.
The activity of the MMPs is furthermore essential for many of the processes which play a role in atherosclerotic plaque formation, such as the infiltration of inflammatory cells and smooth muscle cell migration, as well as proliferation and angiogenesis (S. J. George, Exp. Opin. Invest. Drugs (2000), 9 (5), 993–1007). Furthermore, the degradation of matrix by MMPs can cause anything from plaque instabilities through to ruptures, with these conditions being able to give rise to the clinical symptoms of atherosclerosis, unstable angina pectoris, myocardial infarction or stroke (E. J. M. Creemers et al., Circulation Res. 89, 201–210 (2001)). All in all, the MMP family as a whole is able to break down all the components of the extracellular matrix of the blood vessels; in normal blood vessels, therefore, their activity is to a very great degree subject to regulatory mechanisms. The increase in MMP activity during plaque formation and plaque instability is caused by an increase in cytokine-stimulated and growth factor-stimulated gene transcription, an increase in zymogen activation and an imbalance in the MMP/TIMP (tissue inhibitors of metalloproteases) ratio. It therefore seems plausible that an MMP inhibition or the reattainment of the MMP-TIMP balance, would be helpful in treating atherosclerotic diseases. It is likewise becoming ever more clear that an increase in MMP activity is at least partially responsible for other cardiovascular diseases in addition to atherosclerosis, such as restenosis, dilated cardiomyopathy and the previously mentioned myocardial infarction. It has been shown that administering synthetic inhibitors to experimental animal models of these diseases is able to achieve marked improvements, for example in regard to the formation of atherosclerotic lesions, neointima formation, left ventricular remodeling, pump performance malfunction or infarction healing. In various preclinical studies using MMP inhibitors, detailed tissue analyses indicated a reduction in collagen damage, an improvement in extracellular matrix remodeling and an improvement in the structure and function of cardiac muscle and blood vessels. Among these processes, matrix remodeling processes and MMP-regulated fibroses, in particular, are regarded as being important components in the progression of heart diseases (infarction) (Drugs 61, 1239–1252 (2001)).
Under physiological conditions, MMPs cleave matrix proteins such as collagen, laminin, proteoglycans, elastin or gelatine, and also process (i.e. activate or inactivate), by means of cleavage, a large number of other proteins and enzymes, which means that they play an important role in the entire body, with this role being particularly significant in the connective tissue and bones.
A large number of different MMP inhibitors are known (EP 0 606 046; WO 94/28889; WO 96/27583; cf. reviews such as Current Medicinal Chemistry 8, 425–74 (2001) as well). Following the first clinical studies in humans, it has now been found that MMPs give rise to side-effects. The side-effects to be mentioned are musculoskeletal pain or anthralgias. The prior art makes it clear that it is expected that more selective inhibitors would be able to reduce these side-effects (Yip, page 387, see above). Specificity towards MMP-1 is particularly to be emphasized in this connection since these unwanted side-effects evidently appear to an increased extent when MMP-1 is inhibited.
A disadvantage of the known MMP inhibitors is therefore that they frequently lack specificity. Most MMP inhibitors inhibit many MMPs simultaneously because the catalytic domains of the MMPs possess similar structures. As a consequence, the inhibitors also undesirably affect the enzymes which have a vital function (Massova I, et al., The FASEB Journal (1998) 12, 1075–1095).
In the endeavor to find effective compounds for treating connective tissue diseases, it has now been found that the derivatives which are employed in accordance with the invention are powerful inhibitors of the matrix metalloproteinases MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13 while only having a weak inhibitory effect on MMP-1.